1. ¹Division of Dermatologic Oncology, Department of Dermatology, University of Tuebingen, Tuebingen, Germany
2. ²Abramson Cancer Center of the University of Pennsylvania, Philadelphia, USA
3. ³Institute of Cell Biology and Immunology, University of Stuttgart, Germany

Correspondence: Dr Friedegund E. Meier, Division of Dermatologic Oncology, Department of Dermatology, University of Tuebingen, Liebermeisterstr. 25, Tuebingen D-72076, Germany. E-mail: friedegund.meier@med.uni-tuebingen.de

⁴These authors contributed equally to this work

Received 30 July 2007; Accepted 8 January 2008; Published online 6 March 2008.

Abstract

The RAS–RAF–MEK–ERK and PI3K–AKT–mTOR signaling pathways are activated through multiple mechanisms and appear to play a major role in melanoma progression. Herein, we examined whether targeting the RAS–RAF–MEK–ERK pathway with the RAF inhibitor sorafenib and/or the PI3K–AKT–mTOR pathway with the mTOR inhibitor rapamycin has therapeutic effects against melanoma. A combination of sorafenib (4 M) with rapamycin (10 nM) potentiated growth inhibition in all six metastatic melanoma cell lines tested. The absolute enhancement of growth inhibition rates ranged from 13.0–27.8% in different cell lines (P<0.05, combination treatment vs monotreatment). Similar results were obtained with combinations of the MEK inhibitors U0126 (30 M) or PD98059 (50 M) with rapamycin (10 nM). The combined treatment of melanoma cells with sorafenib and rapamycin led to an approximately twofold increase of cell death compared with sorafenib monotreatment (P<0.05) as assessed by propidium iodide staining and cell death detection ELISA. Moreover, sorafenib in combination with rapamycin completely suppressed invasive melanoma growth in organotypic culture mimicking the physiological context. These effects were associated with complete downregulation of the antiapoptotic proteins Bcl-2 and Mcl-1. Sorafenib combined with rapamycin appears to be a promising strategy for the effective treatment of melanoma and merits clinical investigation.